The Combination Effect of Homoharringtonine and Ibrutinib on FLT3-ITD Mutant Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a highly heterogenous disease and the patients with an internal tandem duplication mutation in FMS-liketyrosine-kinase-3 (FLT3-ITD) have a negative impact on outcome. Finding effective treatment regimens is desperately needed. In this study, we explored the inhibitory effects and mechanism of homoharringtonine (HHT) in combination with ibrutinib on FLT3-ITD mutant AML cells. Consequently, we observed a synergistic inhibitory effect when ibrutinib was combined with HHT to inhibit cell proliferation, induce apoptosis and arrest cell cycle at G0/G1 phase in MV4-11 and MOLM-13 leukemia cells. Our results indicate that the mechanisms of the combination effect are mainly via regulating the STAT5/Pim-2/C-Myc pathway, AKT pathway and Bcl-2 family, activation p21^WAF1/CIP1 and inhibiting CCND/CDK complex protein. Interestingly, synergistic cytotoxicity of ibrutinib and HHT was both dependent of FLT3 and BTK. Here we provide a novel effective therapeutic approach for the treatment of AML patients with FLT3-ITD mutation.